The Interferon-beta (IFN-beta)/SETDB2 Epigenetic Axis Regulates Inflammation And Metabolism In Diabetic Wounds

干扰素-β (IFN-β)/SETDB2 表观遗传轴调节糖尿病伤口的炎症和代谢

• 批准号: 10240278
• 负责人: Katherine Ann Gallagher
• 金额: $ 48.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240278
• 关键词: Amputation; Animal Model; Anti-Inflammatory Agents; Binding; Cells; Cellular Metabolic Process; Chromatin; Chronic; Cytokine Signaling; Data; Development; Diabetes Mellitus; Environment; Enzymes; Epigenetic Process; Event; Evolution; Failure; Gene Expression; Genes; Genetic; Genetic Transcription; Health Care Costs; Healthcare Systems; Histones; Human; Impaired healing; Impaired wound healing; Impairment; Inflammation; Inflammatory; Injury; Interferon-beta; Interleukin-1 beta; Kinetics; Laboratories; Lead; Link; Lysine; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Methyltransferase; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Pharmacology; Phenotype; Plant Roots; Play; Process; Proteins; Regulation; Resolution; Role; STAT1 gene; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Time; Tissues; Up-Regulation; Uric Acid; Work; Wound models; XDH gene; Xanthines; base; cytokine; diabetic ulcer; epigenetic regulation; experimental study; healing; histone modification; improved; innovation; macrophage; mortality; mouse model; new therapeutic target; non-healing wounds; novel; pre-clinical; prevent; promoter; receptor; success; targeted treatment; tissue repair; wound; wound healing; wound treatment

PROJECT SUMMARY/ABSTRACT Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and are increasing at an alarming rate. The factors controlling macrophage function and how these cells transition from an inflammatory to a reparative phenotype in wound tissues are not understood; leaving a large deficit in our ability to prevent and treat these wounds. Our laboratory is investigating novel epigenetic changes, induced via post-transitional modifications of histones, as mechanism(s) to regulate the macrophage phenotype during wound healing. We present data that the cytokine environment established in wounds following injury induces the expression of specific epigenetic machinery in macrophages that control gene transcription, and hence, function. Using human cells and our experimental murine model of wound healing, we have identified that interferon-beta (IFNβ) induces the expression of SETDB2, an epigenetic-based lysine methyltransferase that is responsible for setting a suppressive histone mark that results in the silencing of inflammatory and metabolic genes. This sequence of events is beneficial in normal wound healing, allowing for the transition from an inflammatory to a reparative macrophage phenotype needed to promote healing. We hypothesize that during the evolution of normal wound healing, IFNβ-mediated induction of SETDB2 in wound macrophages represses NFKB-mediated inflammatory and metabolic genes resulting in decreased wound inflammation and enhanced wound repair. We further postulate that this process does not occur in diabetic wounds where SETDB2 is not induced in wound macrophages, resulting in increased inflammation and non-healing wounds. This hypothesis will be investigated via the following specific aims: 1) Elucidate the regulation of NFkB-mediated gene expression by SETDB2 in normal and diabetic wound macrophages; 2) Determine the IFNβ-mediated mechanism(s) that upregulate macrophage-specific SETDB2 expression in normal and diabetic wound tissue; and 3) Establish the role of SETDB2-regulated uric acid on normal and diabetic wound macrophage phenotypes during healing.

项目概要/摘要 2 型糖尿病 (T2D) 患者的伤口不愈合是发病率和死亡率的主要原因 正在以惊人的速度增长。控制巨噬细胞功能的因素以及这些细胞如何转变 伤口组织从炎症到修复表型的过程尚不清楚；留下巨额赤字 我们预防和治疗这些伤口的能力。我们的实验室正在研究新的表观遗传变化，诱导 通过组蛋白的过渡后修饰，作为调节巨噬细胞表型的机制 伤口愈合。我们提供的数据表明，损伤后伤口中建立的细胞因子环境会诱导 巨噬细胞中控制基因转录的特定表观遗传机制的表达，因此， 功能。使用人类细胞和我们的伤口愈合实验小鼠模型，我们发现 干扰素-β (IFNβ) 诱导 SETDB2 的表达，SETDB2 是一种基于表观遗传的赖氨酸甲基转移酶 负责设置抑制性组蛋白标记，从而导致炎症和代谢的沉默 基因。这一系列事件有利于正常的伤口愈合，允许从 炎症到促进愈合所需的修复性巨噬细胞表型。我们假设在 正常伤口愈合的演变，伤口巨噬细胞中 IFNβ 介导的 SETDB2 诱导 抑制 NFKB 介导的炎症和代谢基因，从而减少伤口 炎症和增强伤口修复。我们进一步假设这个过程不会发生在 糖尿病伤口，伤口巨噬细胞中不诱导 SETDB2，导致 炎症和不愈合的伤口。该假设将通过以下具体目标进行研究： 1) 阐明SETDB2在正常和糖尿病伤口中对NFkB介导的基因表达的调节 巨噬细胞； 2) 确定 IFNβ 介导的上调巨噬细胞特异性 SETDB2 的机制 在正常和糖尿病伤口组织中表达； 3) 确定 SETDB2 调节尿酸对 愈合过程中正常和糖尿病伤口巨噬细胞表型。

项目成果

Murine macrophage chemokine receptor CCR2 plays a crucial role in macrophage recruitment and regulated inflammation in wound healing.

• DOI: 10.1002/eji.201747400
• 发表时间: 2018-09
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Boniakowski AE;Kimball AS;Joshi A;Schaller M;Davis FM;denDekker A;Obi AT;Moore BB;Kunkel SL;Gallagher KA
• 通讯作者: Gallagher KA